Post on 11-May-2023
Western UniversityScholarship@Western
Paediatrics Publications Paediatrics Department
4-2017
Unexpected Widespread Hypophosphatemia andBone Disease Associated with Elemental FormulaUse in Infants and ChildrenLuisa F Gonzalez Ballesteros
Nina S Ma
Rebecca J Gordon
Leanne Ward
Philippe Backeljauw
See next page for additional authors
Follow this and additional works at: https://ir.lib.uwo.ca/paedpub
Part of the Pediatrics Commons
Citation of this paper:Gonzalez Ballesteros, Luisa F; Ma, Nina S; Gordon, Rebecca J; Ward, Leanne; Backeljauw, Philippe; Wasserman, Halley; Weber,David R; DiMeglio, Linda A; Gagne, Julie; Stein, Robert; Cody, Declan; Simmons, Kimber; Zimakas, Paul; Topor, Lisa Swartz;Agrawal, Sungeeta; Calabria, Andrew; Tebben, Peter; Faircloth, Ruth; Imel, Erik A; Casey, Linda; and Carpenter, Thomas O,"Unexpected Widespread Hypophosphatemia and Bone Disease Associated with Elemental Formula Use in Infants and Children"(2017). Paediatrics Publications. 57.https://ir.lib.uwo.ca/paedpub/57
AuthorsLuisa F Gonzalez Ballesteros, Nina S Ma, Rebecca J Gordon, Leanne Ward, Philippe Backeljauw, HalleyWasserman, David R Weber, Linda A DiMeglio, Julie Gagne, Robert Stein, Declan Cody, Kimber Simmons,Paul Zimakas, Lisa Swartz Topor, Sungeeta Agrawal, Andrew Calabria, Peter Tebben, Ruth Faircloth, Erik AImel, Linda Casey, and Thomas O Carpenter
This article is available at Scholarship@Western: https://ir.lib.uwo.ca/paedpub/57
Unexpected widespread hypophosphatemia and bone disease associated with elemental formula use in infants and children
Luisa F. Gonzalez Ballesterosa, Nina S. Mab, Rebecca J. Gordonc, Leanne Wardd, Philippe Backeljauwe, Halley Wassermane, David R. Weberf, Linda A. DiMegliog, Julie Gagneh, Robert Steini, Declan Codyj, Kimber Simmonsk, Paul Zimakasl, Lisa Swartz Toporm,n, Sungeeta Agrawalm,n, Andrew Calabriao, Peter Tebbenp, Ruth Fairclothq, Erik A. Imelg, Linda Caseyr,1, and Thomas O. Carpentera,*,1
aYale University School of Medicine, Department of Pediatrics, New Haven, CT, United States bBoston Children's Hospital, Boston, MA, United States cColumbia University Medical Center, New York, NY, United States dChildren's Hospital of Eastern Ontario, Ottawa, ON, Canada eCincinnati Children's Hospital, Cincinnati, OH, United States fUniversity of Rochester, Rochester, NY, United States gRiley Hospital for Children, Indiana University, Indianapolis, IN, United States hCentre Hospitalier de l'Université Laval, Quebec City, QC, Canada iChildren's Hospital of Western Ontario, London, ON, Canada jOur Lady's Children's Hospital, Crumlin, Ireland kChildren's Hospital Colorado, Denver, CO, United States lUniversity of Vermont Medical Center, Burlington, VT, United States mAlpert Medical School of Brown University, Providence, RI, United States nHasbro Children's Hospital, Providence, RI, United States oChildren's Hospital of Philadelphia, Philadelphia, PA, United States pMayo Clinic, Rochester, MN, United States qWalter Reed National Military Medical Center, Bethesda, MD, United States rBritish Columbia Children's Hospital, Vancouver, BC, Canada
Abstract
Objective—Hypophosphatemia occurs with inadequate dietary intake, malabsorption, increased
renal excretion, or shifts between intracellular and extracellular compartments. We noticed the
common finding of amino-acid based elemental formula [EF] use in an unexpected number of
cases of idiopathic hypophosphatemia occurring in infants and children evaluated for skeletal
disease. We aimed to fully characterize the clinical profiles in these cases.
Methods—A retrospective chart review of children with unexplained hypophosphatemia was
performed as cases accumulated from various centres in North America and Ireland. Data were
*Corresponding author at: Yale University School of Medicine, Department of Pediatrics (Endocrinology), P.O Box 208064, LMP 3103; 333 Cedar Street, New Haven, CT 06520-8064, United States. thomas.carpenter@yale.edu (T.O. Carpenter).1Authors LC and TOC contributed equally to this work.
Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.bone.2017.02.003.
DisclosuresThomas O. Carpenter and Linda Casey have performed consulting services for Nutricia, North America. The other authors have indicated they have no financial relationships relevant to this article to disclose.Conflict of interestRuth Faircloth, MD: The views expressed are those of the authors and do not reflect the official policy or position of the US Army, Department of Defense nor the US Government. The other authors have no potential conflicts of interest to disclose.
HHS Public AccessAuthor manuscriptBone. Author manuscript; available in PMC 2018 April 04.
Published in final edited form as:Bone. 2017 April ; 97: 287–292. doi:10.1016/j.bone.2017.02.003.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
analyzed to explore any relationships between feeding and biochemical or clinical features, effects
of treatment, and to identify a potential mechanism.
Results—Fifty-one children were identified at 17 institutions with EF-associated
hypophosphatemia. Most children had complex illnesses and had been solely fed Neocate®
formula products for variable periods of time prior to presentation. Feeding methods varied.
Hypophosphatemia was detected during evaluation of fractures or rickets. Increased alkaline
phosphatase activity and appropriate renal conservation of phosphate were documented in nearly
all cases. Skeletal radiographs demonstrated fractures, undermineralization, or rickets in 94% of
the cases. Although the skeletal disease had often been attributed to underlying disease, most all
improved with addition of supplemental phosphate or change to a different formula product.
Conclusion—The observed biochemical profiles indicated a deficient dietary supply or severe
malabsorption of phosphate, despite adequate formula composition. When transition to an
alternate formula was possible, biochemical status improved shortly after introduction to the
alternate formula, with eventual improvement of skeletal abnormalities. These observations
strongly implicate that bioavailability of formula phosphorus may be impaired in certain clinical
settings. The widespread nature of the findings lead us to strongly recommend careful monitoring
of mineral metabolism in children fed EF. Transition to alternative formula use or implementation
of phosphate supplementation should be performed cautiously with as severe hypocalcemia may
develop.
1. Introduction
Hypophosphatemia is uncommon in childhood and can occur either with or without
depletion of whole-body phosphate [P] stores [1]. In the acute setting, or upon refeeding
after prolonged depletion, phosphate may shift from extracellular to intracellular
compartments resulting in transient hypophosphatemia without phosphate depletion. In the
more chronic setting, long-term phosphate depletion may occur after prolonged inadequate
intake, malabsorption, or excessive urinary losses due to renal tubular disease. As phosphate
is abundant in Western diets, inadequate phosphate supply is rarely encountered in the
United States [US] and Canada, and observed in very specific situations, such as the
breastfed premature infant (owing to the low P content of breast milk). Decreased intestinal
absorption of phosphate may occur with generalized malabsorption, vitamin D deficiency or
due to the use of phosphate binding agents. One such example has been often reported in
individuals abusing antacids, whereby resultant bound phosphate is less available for
intestinal absorption [2]. Alternatively, abnormal renal losses of phosphate may occur in the
setting of hyperparathyroidism, excess fibroblast growth factor 23 [FGF23], or primary
disorders of the renal tubule [1]. Generally, hypophosphatemia encountered in childhood is
accompanied by characteristic historic and/or clinical features that suggest the most likely
etiology.
The composition of nutritional formulas designed for infants and children follows
nationally- and globally-established guidelines to maximize safety and nutritional adequacy
across a variety of intakes [3]. When formula is used as the sole source of nutrition, intake is
determined by energy requirements and micronutrient intake varies accordingly. Despite this
variability in intake, micronutrient intake from formula is usually adequate to meet
Gonzalez Ballesteros et al. Page 2
Bone. Author manuscript; available in PMC 2018 April 04.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
requirements for most nutrients until intakes fall far below expected for age. As such,
micronutrient deficiencies in children consuming infant and pediatric formulas across a wide
range of intakes are rare. Furthermore, when low formula volumes are consumed due to low
energy requirements, intake of all micronutrients is reduced, resulting in potential
deficiencies of multiple micronutrients. Thus isolated micronutrient deficiency in a formula-
fed population is not commonly encountered.
In this manuscript, we describe a series of children who had unexpected and unexplained
hypophosphatemia, and who had in common the consumption of single brand of amino-acid
based nutritional formula.
2. Patients and methods
This was a retrospective chart review conducted in 17 centres in North America and Ireland
between 2014 and 2016. Patients were referred to the various authors because of
unexplained mechanism of marked hypophosphatemia in infants and young children,
sometimes accompanied by significant bone disease. This case series was compiled when it
became evident that several common clinical and biochemical features suggested a
limitation in dietary phosphate intake or its intestinal absorption. After the development of a
data collection form, centres/ clinicians who had contacted the senior authors regarding
affected children provided descriptive details to facilitate comparison of cases. All
biochemical measurements were performed at the individual treating centres' clinical
laboratories. All data was collected and shared in compliance with the ethics requirements of
each centre. After receipt of the supporting information for each case, data was collectively
examined to identify similarities and differences, with the objective of describing clinical
features, identifying potential risk factors and generating hypotheses regarding etiology of
the problem. No cases were excluded because of the use of any particular formula products.
Selected clinical case vignettes are provided as examples. (Further details enumerating all
cases are found in the Supplementary Table S1).
3. Results
3.1. Cases
3.1.1. Case vignette 1—An 18 month-old boy had a history of esophageal atresia/
tracheoesophageal fistula repair and necrotizing enterocolitis. He was orally fed, receiving
diuretics and glucocorticoids, and was relatively immobile. After 1 year of Neocate®
feeding, he demonstrated irritability associated with knee and skeletal manipulation. A
radiographic skeletal survey showed numerous fractures including those of the femur,
fibulae, ulna, metatarsals, a metacarpal, and 3 ribs. Upon identification of a low blood P
level (1.3 mg/dL; 0.40 mM) and elevated alkaline phosphatase (1137 IU/L), he was treated
with calcitriol and oral phosphate. Subsequently the formula was changed to Elecare®, and
phosphate supplementation was discontinued, with continue maintenance of a normal serum
phosphorus level without added phosphate supplementation. Correction of serum alkaline
phosphatase ensued and after 3 months, radiographs improved.
Gonzalez Ballesteros et al. Page 3
Bone. Author manuscript; available in PMC 2018 April 04.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
3.1.2. Case vignette 2—A 4-year old girl with a history of hypoxic ischemic
encephalopathy, gastric dysmotility, developmental delay and seizures had received Neocate
Jr® for 2.6 years. Prior to presentation, she had decreased mobility, and had stopped all
crawling and weight-bearing. Healing rib fractures were observed on radiographic
examination of the chest; subsequent biochemical evaluation revealed low blood P (1.7
mg/dL; 0.53 mM) and elevated alkaline phosphatase levels (1014 IU/L). She was then
treated with oral phosphate supplements, and the formula was changed to Pediasure®.
Phosphate supplementation was then discontinued with continued maintenance of a normal
serum phosphorus level, and correction of alkaline phosphatase.
3.1.3. Case vignette 3—A 3.5-month old girl (born after a 28 week gestation) with
bronchopulmonary dysplasia had a history of feeding intolerance with abdominal distention,
which led to feeding with various formulas until milk protein allergy was diagnosed at 2
months of age, when nasogastric Neocate® feeds were begun. Incidental biochemical testing
performed 6 weeks later revealed low serum P (2.9 mg/dL; 0.90 mM) and elevated alkaline
phosphatase levels (796 IU/L). She was briefly provided with oral phosphate, then changed
to Alimentum® formula. Phosphate supplementation was discontinued with maintenance of
normal serum P level, and correction of alkaline phosphatase.
3.1.4. Case vignette 4—An 8 month-old girl, born after a 31 week gestation, had been
fed Neocate® since age 2 months due to a diagnosis of milk protein allergy. She had a
history of retinopathy of prematurity, microcephaly, reflux, and hypertonia, and presented
after 6 months of elemental formula exposure with a left tibia fracture in the absence of any
history of recent trauma. Investigation revealed hypophosphatemia (2.9 mg/dL; 0.90 mM)
and elevated alkaline phosphatase levels (1510 IU/L). The formula was changed to
Elecare®, with correction of the serum phosphorus level, and alkaline phosphatase activity
(Fig. 1). No supplemental phosphate was administered.
3.1.5. Case vignette 5—A 6.5 year-old boy presented to the emergency room with
respiratory distress and decreased movement of his right arm for 2 weeks. Severe
hypophosphatemia was identified incidentally (serumP, 0.6 mg/dL). He had a history of
epidermolysis bullosa and profound global developmental delay. He had been fed Neocate®
formula via gastrostomy tube since 3 years of age. Rickets and healing fractures were noted
radiographically and phosphate supplementation was begun. One year later, Neocate®
formula was changed to Elecare® with subsequent normalization of the serum P level
without phosphate supplementation (see Table 1), however persistent diarrhea prompted a
change back to Neocate® formula feeds. Two weeks after the resumption of Neocate®
feedings, the serum P level decreased to 1.2 mg/dL, requiring the resumption of phosphate
supplementation. A second attempt to use Elecare® two months later was well-tolerated,
and coincident correction of the serum P level occurred. Eventually radiographic features of
rickets healed.
3.2. Chart review
Fifty-one children were identified from17 centres in the US, Canada and Europe.
Demographic features, and selected clinical characteristics are listed in Table 2. Age at the
Gonzalez Ballesteros et al. Page 4
Bone. Author manuscript; available in PMC 2018 April 04.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
time of identification ranged from 0.2 to 15.5 years (median, 3.0). Fifty-seven percent of
these children were female and 43% were male. Most children (96%) were investigated
because of rickets or unexplained single or multiple fractures. The remaining 4% were
detected upon biochemical laboratory screening. All identified children were receiving
Neocate® formula products as their sole source of nutrition. The formula was administered
either via oral or intragastric routes (53%), via the transpyloric route (37%) or using both
gastric and transpyloric routes (10%). Median duration of Neocate® feeding was 1.3 years
(range 1 week to 8 years). All affected children had complex but highly variable medical
histories (see Supplementary Table S1), without a single unifying explanatory feature.
Documentation of medication use was available for 44 children (86%), and of these, 91%
were exposed to medications that modify gastric acidity, usually proton pump inhibitors
[PPIs], with one case of histamine receptor 2-blocker use. Height or length was at the third
centile or less for age in 49% of children, and at tenth centile or less in 61%. Weight was at
the third centile or less for age in 41% of children, and at tenth centile or less in 49%.
The results of laboratory investigations were remarkably consistent in all identified children
(Table 3). The most striking features were markedly decreased serum phosphate, elevated
alkaline phosphatase and normal 25 hydroxyvitamin D [25-OHD] levels. In most cases,
serum phosphate and alkaline phosphatase values were far outside of reference ranges.
Calcium (ionized and/or total) and PTH levels were usually in the normal range. Urinary
phosphate was undetectable or extremely low in all cases, and tubular reabsorption of
phosphate (TRP) [4] approached 100% when it could be calculated from the available data.
When 1,25 dihydroxyvitamin D [1,25(OH)2D] had been measured (n=37), it was
consistently and significantly elevated, and thus may be a highly sensitive biomarker for this
phenomenon. Circulating FGF23 levels (measured in only two cases) were low.
Various therapeutic approaches were employed across the multiple patients and centres, and
evolved with increasing experience with the management of the cases. Initially, phosphorus
supplementation was employed with continued use of Neocate® formula in most cases
(75%). Calcium, vitamin D, and/or calcitriol were occasionally required, to treat severe
hypocalcemia, which often occurred rapidly following the addition of phosphate
supplements (Fig. 1). In other cases (25%) the formula product was substituted with breast
milk, alternate formula products, or parenteral feeds. As with supplemental phosphate
administration, hypocalcemia was also often precipitated when the formula product was
substituted. Overall, 47% of the children developed hypocalcemia following intervention,
and was occasionally severe. In one case, severe hypocalcemia may have contributed to a
seizure episode and a subsequent cardiac arrest. After observing the correction of
hypophosphatemia with formula product changes, several patients originally treated with
phosphate also underwent changes in formula as to simplify their medication regimens.
Nevertheless, four cases were intolerant of formula change (diarrhea or anaphylaxis) and
required resumption of Neocate® with added phosphate supplements. A representative
example of the biochemical and radiographic changes occurring at presentation and with
application of treatment is shown in Figs. 1 and 2. In other cases, hypophosphatemia was
evident as early as one week after the introduction of Neocate®, but was not recognized
until several months later.
Gonzalez Ballesteros et al. Page 5
Bone. Author manuscript; available in PMC 2018 April 04.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Overall, biochemical abnormalities resolved when supplements were introduced or formula
was changed, and bone disease improved with continued therapy. In all cases where frequent
follow up data is available, correction of the serum P occurred within 2–7 days after
intervention, however no systematic determination of the rapidity of this correction was
possible. Decrements in the elevated serum alkaline phosphatase values occurred within
weeks, but the correction to the normal range was quite variable and may reflect the
chronicity of precedent hypophosphatemia and severity of the bone disease. Radiographic
improvement of rachitic disease was often evident by 4–8 weeks when X-ray images were
available in this time frame.
4. Discussion
We describe a cohort of infants and children with previously unrecognized
hypophosphatemia accompanied in most cases by significant bone disease. All had in
common the use of amino-acid based infant or pediatric formulas. The formulas were
prepared by a single manufacturer (Nutricia: Neocate Infant®, Neocate Junior®, and
Neocate Advance®), although the possibility that hypophosphatemia may occur with other
amino-acid based formulas cannot be excluded. Review of records from several patients in
the series documented hypophosphatemia early in the course of formula use, but was not
initially interpreted as related to the feedings. As some features had been evident several
years prior to this analysis, it is unlikely that alterations in formulation or manufacturing
processes account for the findings. It is presently unclear why some children experience the
complication while others do not. Preliminary findings from a recent prospective study
found no significant mineral deficiencies when Neocate® was used in children with isolated
milk protein allergy and who were otherwise healthy [5].
The patients that we describe have in common complicated and diverse clinical histories
without obvious unifying features. Many, but not all, were born prematurely, though
hypophosphatemia was often observed far beyond the neonatal period. The majority were
affected with gastro-intestinal diagnoses. Most were tube-fed via gastric or post-pyloric
routes. Thus the hypophosphatemia may reflect an as yet unidentified interaction between
patient factors and formula. The formula products used would be expected to meet or exceed
recommended intakes of all minerals, including phosphorus. For instance Neocate Infant®
formula contains 82.2 mg of phosphorus per 100 kcal [6], yet hypophosphatemia occurred.
This is comparable to the phosphorus content of alternate amino acid formulas (Elecare®
contains 84.2 mg of phosphorus/100 kcal).
The biochemical profile in all infants strongly suggests limited intestinal absorption of
phosphate. The maximal renal conservation of phosphate documented in most cases at the
time of diagnosis is a normal physiologic response to phosphate depletion, and excludes
renal phosphate losses as causal. The marked elevation in circulating 1,25(OH)2D levels is a
classic endocrine response to phosphate deprivation [7]. In two cases where available,
circulating FGF23 levels were in the low range, as would be expected to occur with
inadequate dietary phosphate, and allowing for the increase in 1,25(OH)2D.
Gonzalez Ballesteros et al. Page 6
Bone. Author manuscript; available in PMC 2018 April 04.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Although these findings implicate that the hypophosphatemia resulted from reduced mineral
bioavailability from the formula, an underlying mechanism remains unclear. Furthermore,
the marked elevation in serum phosphorus following phosphate supplementation or formula
change suggests a robust capacity of the native intestine to absorb phosphate when an
alternate form of the mineral is provided. The hyperphosphatemia in this acute setting is
likely explained by upregulation of Na-Pi2b sodium-phosphate cotransporters in the
intestine, as would occur during phosphate starvation [8]. The accompanying low urinary
phosphate excretion is best explained by upregulation of renal tubular Na-Pi2a and Na-Pi2c
cotransporters, a well-known adaptation to phosphate starvation [9]. As it takes some time to
downregulate these adaptive responses, the marked increase in serum phosphorus acutely
after provision of a bioavailable form of the mineral would be predicted to occur, as the
upregulated transporters would allow for robust intestinal absorption and renal tubular
reabsorption of phosphate, compromising the capacity to excrete the newly acquired
phosphate load.
Mineral solubility is a well-recognized problem in the preparation of parenteral nutrition
solutions, affected by concentrations of calcium, phosphorus and amino-acids, as well as
temperature and pH [10]. As precipitation issues are not evident with many formulas of
similar mineral content, formula mineral concentration is not a likely explanation, however
phosphate used in Neocate is listed as dibasic calcium phosphate, whereas calcium
phosphate and potassium phosphate are used in Elecare, so differences exist in the species of
phosphate salts employed in these formulas. Moreover, pH impacts mineral solubility and
may vary from patient to patient, giving rise to variable clinical presentation, and the pH of
the environment into which formula is delivered could significantly impact mineral
solubility in vivo. Many children in this series were treated with gastric acid modifying
agents, mostly PPI medications, likely resulting in greater than physiologic gastric pH.
Nevertheless, no identifiable measures of systemic acid/base abnormalities were
accompanied by these findings. Furthermore, correction of phosphate status occurred
without alteration of acid-modifying (or other) medications. In addition, several children
were fed postpylorically where the local pH is expected to be neutral [11]. Increasing pH
(particularly in the non-acid range) adversely affects calcium and phosphate solubility and
offers an attractive hypothesis for the apparently impaired mineral absorption [10]. A
preliminary study describes 4 cases of hypophosphatemia in association with high doses of
PPI medications in children receiving gastrostomy tube feedings [12], however, formula use
was not reported. In our series formula change and/or phosphate supplementation resulted in
correction of the serum phosphorus level while patients continued to receive acid-modifying
agents. In case vignette 5, the reappearance of hypophosphatemia when Neocate formula
was re-introduced after brief discontinuation emphasizes the peculiar association of the
Neocate formula and hypophosphatemia. Another consideration is the possibility that
materials in feeding tubes could bind to phosphate products, thereby affecting delivery of
phosphate to the child, however this seems unlikely in view of the multiplicity of centres
identifying the problem, and the use of various feeding methods (via gastrostomy, as well as
oral, nasogastric, and transpyloric feeds). Case vignette 5 describes the occurrence of
hypophosphatemia with a specific formula, which was not evident after a formula change
using the same feeding method.
Gonzalez Ballesteros et al. Page 7
Bone. Author manuscript; available in PMC 2018 April 04.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
As this condition has not previously been described and optimal management is unknown,
the treatment of children in this series varied considerably. Biochemical findings and bone
radiographs improved with mineral supplementation, or formula change. We have not
identified any specific differences among these formulas that would explain a potential
difference in the bioavailability of phosphate. Caution is necessary in initiating phosphate
supplementation or transition to a new formula and should be done gradually to avoid severe
hyperphosphatemia and hypocalcemia. The “hungry bone” syndrome may further compound
this phenomenon as rapid skeletal mineralization ensues [13]. Continued monitoring to
ensure clinical improvement, normalization of biochemical abnormalities is indicated, and
periodic follow up is warranted to avoid recurrent abnormalities.
It appears from an increasing recognition of cases that the problem is not sporadic. After
bringing this issue to the attention of the manufacturer, a statement was issued directed to
prescribers of the formula recommending periodic monitoring of serum levels of
micronutrients, including phosphate, in children with complex diseases [14]. We recommend
periodic measurement of serum phosphorus, calcium and alkaline phosphatase; potential
benefits of early identification and treatment of the condition would be predicted to offset
the small costs of screening, at least until specific risk factors can be delineated. In children
with overt clinical findings such as linear growth failure, radiologic osteopenia, rickets or
fractures, a more extensive evaluation is indicated, including measurement of serum
phosphorus, calcium, creatinine, alkaline phosphatase, 25-OHD and PTH. Assessment of
urinary phosphorus and creatinine excretion and calculation of the tubular reabsorption of
phosphate provide definition of renal phosphate handling, and measurement of serum
1,25(OH)2D may serve as a corroborative test.
Limitations of this study include its retrospective nature, and the primarily descriptive data
available. The lack of uniformity in the data collection makes it difficult to establish a
necessary duration of exposure for the development of the condition. These constraints also
preclude the identification of a specific mechanism for the finding, however the physiologic
markers identified were sufficient to lead clinicians to management directed toward
enhancing the nutritional phosphorus supply, which successfully corrected the condition.
Finally, we cannot confirm a distinct host factor(s) which may contribute to the presumed
impairment in phosphate availability, and can only speculate in this regard.
5. Conclusion
Clinicians should be aware of the potential for significant hypophosphatemia and bone
disease in children receiving amino-acid based formula products (especially Neocate®), and
particularly those with medically complex conditions receiving formula as their sole source
of nutrition. The children in this series were managed with supplemental phosphate or
alternative formula products, implicating reduced bioavailability of phosphorus in the
formula for certain individuals. Patient-related risk-factors, and an understanding of the
mechanism by which the availability of the phosphate provided in the formula is limited or
compromised require further investigation.
Gonzalez Ballesteros et al. Page 8
Bone. Author manuscript; available in PMC 2018 April 04.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
We thank Dr. Renee Mobley for her assistance with preparation of the graphic material and Drs. Mobley and Melinda Sharkey for informative and instructive discussion.
Funding source
Dr. Gordon was funded in part by NIH/NIDDK grant T32DK065522. No other funding was secured for this study.
References
1. Imel EA, Econs MJ. Approach to the hypophosphatemic patient. J. Clin. Endocrinol. Metab. 2012; 97(3):696–706. [PubMed: 22392950]
2. Insogna KL, Bordley DR, Caro JF, Lockwood DH. Osteomalacia and weakness from excessive antacid ingestion. JAMA. 1980; 244(22):2544–2546. [PubMed: 7431592]
3. Food and Agricultural Organization of the United Nations, World Health Organization. [Last accessed May 5, 2016] Standard for infant formula and formulas for special medical purposes intended for infants; Codex Stan 72, Codex Alimentarius. International Food Standards. 1981. www.fao.org/input/download/standards/288/CXS_072e_2015.pdf
4. Ardeshirpour L, Cole DEC, Carpenter TO. Evaluation of bone and mineral disorders. Pediatr. Endocrinol. Rev. 2007; 5(Suppl. 1):584–598. [PubMed: 18167468]
5. Harvey BM, Harthoorn LF, Burks AW. Mineral status of infants requiring dietary management of cow's milk allergy by using an amino acid-based formula. World Congress of Pediatric Gastroenterology, Hepatology and Nutrition (WCPGHAN), Montreal Canada. J. Pediatr. Gastroenterol. Nutr. 2016; 63(Suppl. 2):S399. (1172).
6. Nutricia products guide/website. http://nutricia.com/our-products/paediatrics-nutrition/neocate/what-is-neocate
7. Prié D, Friedlander G. Reciprocal control of 1,25-dihydroxyvitamin D and FGF23 formation involving the FGF23/Klotho system. Clin. J. Am. Soc. Nephrol. 2010; 5(9):1717–1722. [PubMed: 20798257]
8. Hattenhauer O, Traebert M, Murer H, Biber J. Regulation of small intestinal Na-Pi type IIb cotransporter by dietary phosphate intake. Am. J. Phys. 1999; 277(4):G756–G762.
9. Blaine J, Weinman EJ, Cunningham R. The regulation of renal phosphate transport. Adv. Chronic Kidney Dis. 2011; 1(2):77–84.
10. MacKay M, Jackson D, Eggert L, Fitzgerald K, Cash J. Practice-based validation of calcium and phosphorus solubility limits for pediatric parenteral nutrition solutions. Nutr. Clin. Pract. 2011; 26(6):708–713. [PubMed: 22205559]
11. Ovesen L, Bendtsen F, Tage-Jensen U, et al. Intraluminal pH in the stomach, duodenum, and proximal jejunum in normal subjects and patients with exocrine pancreatic insufficiency. Gastroenterology. 1986; 90(4):958–962. [PubMed: 3949122]
12. Wolfe-Wylie, M., Mouzaki, M., Sochett, E., Harrington, J. Chronic high dose proton-pump inhibitors as a cause of hypophosphatemic rickets. Abstract at Endocrine Society's 98th Annual Meeting and Expo. Apr 1–4. 2016 (Boston http://press.endo-crine.org/doi/10.1210/endo-meetings.2016.BCHVD.16.FRI-348)
13. Witteveen JE, van Thiel S, Romijn JA, Hamdy NA. Hungry bone syndrome: still a challenge in the post-operative management of primary hyperparathyroidism: a systematic review of the literature. Eur. J. Endocrinol. 2013; 168(3):R45–R53. [PubMed: 23152439]
14. Update on monitoring micronutrients. Nutricia learning center website. http://www.nutricialearningcenter.com/globalassets/pdfs/gi-allergy/update-on-monitoring-micronutrients_mar2016.pdf
Gonzalez Ballesteros et al. Page 9
Bone. Author manuscript; available in PMC 2018 April 04.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Fig. 1. Changes in serum calcium (blue), phosphorus (pink) and alkaline phosphatase (purple) in an
8 month-old girl fed Neocate® since age 2 months due to milk protein allergy, presenting
with a tibial fracture. After the formula was changed to Elecare®, serum phosphorus and
alkaline phosphatase levels corrected. Supplemental phosphate was not administered.
Gonzalez Ballesteros et al. Page 10
Bone. Author manuscript; available in PMC 2018 April 04.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Fig. 2. Radiographs showing severe rickets at presentation (left) and improvement 5 weeks after
formula change (right).
Gonzalez Ballesteros et al. Page 11
Bone. Author manuscript; available in PMC 2018 April 04.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Gonzalez Ballesteros et al. Page 12
Table 1
Serum P relationship to formula and phosphate supplementation.
Date Serum P (mg/dL) Formula Formula change Phosphate supplementation
11/30/14 0.6 Neocate®
12/2014 Neocate® Supplementation added
11/2015 2.5–3.5 Neocate® to Elecare® Began tapering
12/1/15 4.5 Elecare® Off
2/25/2016 Elecare® to Neocate®
3/10/16 1.2 Neocate® Supplementation resumed
3/16/16 3.7 Neocate® On
5/2016 Neocate® to Elecare® Began tapering
8/24/16 4.1 Elecare®
10/26/16 4.7 Elecare®
Bone. Author manuscript; available in PMC 2018 April 04.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Gonzalez Ballesteros et al. Page 13
Table 2
Clinical characteristics.
Clinical characteristics Total/percentage
Age Range: 0.2–15.5 years Median: 3.0
Gender Female 29/57%
Male 22/43%
Growth Height/length ≤ 3rd centile 25/49%
Weight ≤ 3rd centile 21/41%
Formula Infant 15/29%
Junior 35/69%
Advance 1/2%
Feeding route Oral/gastric 27/53%
Jejunal 19/37%
Gastric and jejunal 5/10%
PPI use Data available in 44 patients 40/91%
Primary treatment Phosphate supplements 38/75%
Formula change 13/25%
Abbreviation: PPIs, proton pump inhibitors.
Bone. Author manuscript; available in PMC 2018 April 04.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Gonzalez Ballesteros et al. Page 14
Table 3
Biochemical profile.
Biochemical profile
Mean (SD) Reference values
Serum Ca (mg/dL) 9.6 (0.8)a 8.8–10.2
P (mg/dL) 2.1 (0.7) 1–12 months: 3.0–7.5
1–11 years: 3.5–6.5
11–15 years: 3.5–5.3
Alk Phos (IU/L) 1123 (586) 1 month–6 years: 80–380
6–12 years: 60–480
12–15 years: 90–570 (male)
60–280 (female)
PTH (pg/mL) 39 (22, median) 10–69
25-OHD (ng/mL) 37 (14) 20–50
1,25(OH)2D (pg/mL) 254 (124) <30 days: <10–72
1 month–17 years: 15–90
Urine TRP (%)b 98 (3) <0.25 years: 61–86
0.3–0.5 years: 68–93
0.6–1 year: 80–89
1–2 years: 78–93
3–10 years: 81–98
11–15 years: 86–99
TRP% = 1 − Urinary Phosphate×Serum creatinineSerum Phosphate×Urinary creatinine × 100.
Abbreviations: Ca, calcium; P, phosphate; Alk Phos, alkaline phosphatase; PTH, parathyroid hormone; 25-OHD, 25 hydroxyvitamin D; 1,25(OH)2 D, 1,25 dihydroxyvitamin D; SD, standard deviation; TRP, tubular reabsorption of phosphate. [Reference range for 1,25(OH)2D is that in use at
ESOTERIX/LabCore; reference ranges for all other serum values are those in use at Yale-New Haven Hospital. Values for TRP are those reviewed by Ardeshirpour [4].
aValues are in Mean (SD, unless otherwise indicated).
bn= 9 where calculable, 25 had undetectable urinary P.
Bone. Author manuscript; available in PMC 2018 April 04.